Using Genetics to Prevent Chemotherapy Side Effects

When President Bill Clinton announced the completion of the first draft of the human genome in 2000, he said it would “revolutionize the diagnosis, prevention and treatment of most, if not all, human diseases.” At the time, the hope was that the Human Genome Project would uncover the roots of common diseases like cancer or diabetes. While that hasn’t happened yet, researchers have sequenced more than 1,000 genomes since then, and have learned a great deal about how different genetic variations are linked (or not linked at all) to disease.

One important area of research made possible by a better understanding of the human genome is pharmacogenomics, the study of how genetics affect a patient’s response to medications. Why do certain drugs work for some patients and not others? Why do some patients suffer severe side effects, while others tolerate a drug relatively well? Those are some of the questions scientists working in pharmacogenomics hope to answer, to realize the potential of “personalized medicine” that tailors treatment and medications specifically for a patient’s unique genetic makeup.

Eileen Dolan, PhD, professor and chair of the Committee on Clinical Pharmacology and Pharmacogenomics in the University of Chicago Biological Sciences Division, studies the genetic variants responsible for making someone more or less sensitive to chemotherapy drugs. Chemotherapy can often cause severe side effects, such as bone marrow suppression, hearing loss and peripheral neuropathy, which is nerve damage that causes pain and weakness in the muscles and limbs. These side effects can be so debilitating that doctors drop the dosage of the drug to lessen the symptoms, which affects treatment because the patient isn’t getting the same therapeutic benefits of the drug.

Dolan and her colleagues use cell-based models to study the effects of chemotherapy drugs and determine which genetic variations within the DNA of the cells are linked to greater sensitivity to the drug. Using hundreds of cell lines derived from individuals within families, within populations and among different populations of people, the researchers expose them to chemotherapy drugs and test their sensitivity. Then, using what they know about the genetic makeup of those cells, they can look for similarities among the cell lines that were very sensitive to a drug.

The idea is that if doctors know a certain genetic variant is associated with greater sensitivity to a particular chemotherapy drug, they can be more proactive about preventing and treating its side effects, or use a different drug if one is available. “I think we can really impact the quality of life of patients if we’re able to do this up front,” Dolan said. “You don’t want irreversible damage from these drugs, so you’d like to prevent that from occurring.”

Dolan also said this could lead to better treatment of side effects. “If you’re able to understand which genes are most relevant for neuropathy, then scientists can develop more effective drugs that would prevent it, or treat it once it occurs,” she said. “Eventually the hope is that we will have some kind of drug to give to patients to overcome these toxicities.”

Dolan and her colleagues work closely with the University of Chicago Medicine’s Center for Personalized Therapeutics, which seeks to translate pharmacogenomic advances into improved care for patients. They compare the findings of their cell-based studies with the results of clinical trials conducted by the center to validate what truly causes certain reactions to drugs in patients.

“We have a lot of unique expertise at the University of Chicago, and because it’s such a collaborative environment it allows you to do things that you wouldn’t be able to pull off on your own,” Dolan said. It’s that kind of collaboration and expertise that could help researchers like Dolan deliver on some of the revolutionary promises made possible by decoding the human genome.

To learn more about the field of pharmacogenomics, read the review article published by Eileen Dolan and her colleagues in “Trends in Genetics.”